Intrahepatic IL-8 Producing Foxp3⁺CD4⁺ Regulatory T Cells and Fibrogenesis in Chronic Hepatitis C

J Hepatol. 2013 Aug;59(2):229-35. doi: 10.1016/j.jhep.2013.04.011. Epub 2013 Apr 23.

Abstract

Background & aims: Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions.

Methods: Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C.

Results: We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody.

Conclusions: Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.

Keywords: CCL2; Fibrogenesis; Foxp3; GARP; HCV; HSC; Hepatic stellate cells; Hepatitis C virus; IL-8; MMP2; RT-PCR; Regulatory T cells; T effector cells; TIMP1; Teffs; Tregs; alpha-SMA; alpha-smooth muscle actin; chemokine ligand 2; forkhead box P3; glycoprotein A repetitions predimonant; hepatitis C virus; mRNA; matrix metalloproteinases 2; messenger RNA; primary human hepatic stellate cells; real-time polymerase chain reaction; regulatory CD4(+) T cells; tissue inhibitor of metalloproteinases 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Adult
  • Aged
  • Biomarkers / metabolism
  • Disease Progression
  • Female
  • Fibrosis
  • Forkhead Transcription Factors / metabolism
  • Hepatic Stellate Cells / immunology
  • Hepatic Stellate Cells / metabolism
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / pathology*
  • Humans
  • Interleukin-8 / biosynthesis*
  • Liver / immunology
  • Liver / pathology
  • Male
  • Middle Aged
  • T-Lymphocytes, Regulatory / classification
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Up-Regulation
  • Young Adult

Substances

  • Biomarkers
  • CXCL8 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-8